The insulin receptor is encoded by a single copy gene located on chromosome 19 in the human. In addition, two other homologous genes have been identified. One gene encodes the type 1 insulin-like growth factor (IGF) receptor. The third gene in the family encodes an orphan receptor tyrosine kinase named the insulin receptor-related receptor (IRR). We have cloned the cDNA molecules encoding human and mouse IRR. Generally, the predicted structure of IRR is similar to those of the receptors for insulin and IGF-1. In the case of human IRR, we detected a splicing variant in which 24 nucleotides from the 3'-end of intron 13 are included between the sequences of exons 13 and 14. Two observations suggest that this alternatively spliced form may not be physiologically important. First, this variant species of IRR mRNA represents <10% of IRR mRNA in adult human kidney. Second, this splicing variant is not evolutionarily conserved; although there is a potential alternate splice acceptor site 23 nucleotides from the end of intron 13 in mouse IRR, this alternate splicing pattern would be predicted to shift the reading frame. Several variant splicing patterns were observed in the region of the junction between exons 1 and 2 of mouse IRR. None of these variant species of mouse IRR mRNA conserved the open reading frame. Inasmuch as they are not predicted to encode functional IRR molecules, it is unlikely that they are physiologically significant. When IRR cDNA is expressed by transfection in NIH-3T3 cells, the IRR precursor undergoes post- translational processing steps including N-linked glycosylation and proteolytic cleavage into distinct alpha and beta subunits. When cells expressing recombinant IRR are incubated with vanadate (an inhibitor of phosphotyrosine phosphatases), this leads to an increase in the phosphotyrosine content of IRR. However, the phosphotyrosine content of IRR is not increased by incubating the cells with insulin, IGF-1, or proinsulin. Further investigations are underway to attempt to identify the natural ligand for IRR, and to determine the physiological role of IRR.